In humans, free glucose is present in the plasma and interstitial fluid at a concentration of approximately 80 mg per 100 ml. Blood glucose levels; however, are in a dynamic flux. Organs of the body remove the glucose from the blood for metabolic energy, while food intake loads glucose into the blood system. Under normal conditions, the body maintains a balance of blood glucose by absorbing excess glucose into many tissues.
A rise in blood glucose is normally followed by a rise in blood insulin. Insulin secretion is stimulated by many events associated with glucose intake. Primarily, insulin is secreted by the pancreas. High glucose concentration in the vicinity of the .beta.cells of the pancreas is sensed by the glucose transporter GLUT-2 and is carried into the cells. The glucose is modified and begins a signal transduction cascade that results in insulin exocytosis.
Rising concentrations of insulin in the blood have an effect on three main tissues—liver, muscle and adipose tissue. Liver tissues play a central role in glucose homeostasis primarily orchestrated by insulin (Saltiel, A. R. & Kahn, C. R. Nature 414: 799-806 (2001), Michael, M. D. et al. Mol Cell 6: 87-97 (2000)), although it is not well understood how the insulin-elicited signals are tightly controlled in hepatocytes.
In general, insulin activates a four-subunit transmembrane receptor (insulin receptor) expressed on the surface of these tissue types. The activated insulin receptor phosphorylates and recruits different substrate adaptors such as the Insulin Receptor Substrate (IRS) family of proteins. IRS-1 and IRS-2 proteins are known to be positively required for relay of signals emanating from insulin receptor (Araki, E. et al. Nature 372: 186-90 (1994), Tamemoto, H. et al. Nature 372: 182-6 (1994), Withers, D. J. et al. Nature 391: 900-4 (1998)).
Tyrosine phosphorylated IRS displays binding sites for numerous signaling partners. Among them, PI3K has a role in insulin function mainly characterized by the activation of the Akt/PKB and the PKC.zeta. cascades. These cascades are associated with glucagon synthesis and with glucose uptake. Glucose uptake is mediated by the translocation of glucose transport vesicles to the plasma membrane, which is regulated by numerous signal cascades including those discussed.
Grb2-associated binder 1 (Gab1) is part of a family of adaptor proteins recruited by a wide variety of receptor tyrosine Kinases, such as the insulin receptor. Upon stimulation of the receptor by its cognate ligand, Gab is recruited to the plasma membrane, undergoes phosphorylation and functions as a multi protein assembly center. Gab1 shares structural and functional homology with the IRS family of proteins, possessing a PH domain at the N-terminus, multiple tyrosine phosphorylation sites and proline-rich motifs for entertaining SH2- and SH3-containing proteins (Holgado-Madruga, M., et al. Nature 379: 560-4 (1996), Gu, H. & Neel, B. G Trends Cell Biol 13: 122-30 (2003)). Homozygous Gab1 mutant mice are embryonic-lethal, with the phenotype revealing an essential role of Gab1 in promoting signals from epidermal growth factor (EGF) and hepatocyte growth factor (HGF), etc (Sachs, M. et al. J Cell Biol 150: 1375-84. (2000), Itoh, M. et al. Mol Cell Biol 20: 3695-704 (2000)).
The insulin signalling pathway is critical for the regulation of intracellular and blood glucose levels (glucose homeostasis), and dysregulation of glucose homeostasis is indicated in numerous disorders. For example, diabetes mellitus is a group of diseases characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. There are two main forms of diabetes; type 1 and type 2. Type 1 patients are unable to produce insulin, and thus must receive exogenous insulin to survive. On the other hand, type 2 patients have at least partially preserved insulin production, but often are insulin resistant. Insulin resistance is caused by defects that may arise at the insulin receptor or post-insulin receptor levels. Post-insulin receptor defects often involve signal transduction proteins.
For the year 2003, the Center for Disease Control estimates that 17 million Americans have some type of diabetes, with an increasing prevalence during the last decade resulting in an incidence of about 1 million new cases per year. The prevalence and incidence of diabetes is even higher world wide, making diabetes a global health problem. Diabetes is the sixth leading cause of death in the United States.
The primary treatment for diabetes is the delivery of exogenous insulin via pumps and/or injection. Total annual costs for treating diabetes is $132 billion, with $92 billion attributed to direct medical costs.
Thus, there exists in the art a need to develop novel treatments for managing glucose homeostasis and blood glucose levels. There also exists in the art, a need to prevent the dysregulation of glucose homeostasis and blood glucose levels. Thus, there is a need in the art to better understand the insulin signaling pathway and Gab1.